Upstream regulation of the Hippo-Yap pathway in cardiomyocyte regeneration

The response of the adult mammalian heart to injury such as myocardial infarction has long been described as primarily fibrotic scarring and adverse remodeling with little to no regeneration of cardiomyocytes. Emerging studies have challenged this paradigm by demonstrating that, indeed, adult mammalian cardiomyocytes are capable of completing cytokinesis albeit at levels vastly insufficient to compensate for the loss of functional cardiomyocytes following ischemic injury. Thus, there is great interest in identifying mechanisms to guide adult cardiomyocyte cell cycle re-entry and facilitate endogenous heart regeneration. The Hippo signaling pathway is a core kinase cascade that functions to suppress the transcriptional co-activators Yap and Taz by phosphorylation and therefore cytoplasmic retention or phospho-degradation. This pathway has recently sparked interest in the field of cardiac regeneration as inhibition of Hippo kinase signaling or overdriving the transcriptional co-activator, Yap, significantly promotes proliferation of terminally differentiated adult mammalian cardiomyocytes and can restore function in failing mouse hearts. Thus, the Hippo pathway is an attractive therapeutic target for promoting cardiomyocyte renewal and cardiac regeneration. Although the core kinases and transcriptional activators of the Hippo pathway have been studied extensively over the last twenty years, the regulatory inputs of this pathway, particularly in vertebrates, are poorly understood. Recent studies have elucidated several upstream regulatory inputs to the Hippo pathway in adult mammalian cardiomyocytes that influence cell proliferation and heart regeneration. Considering upstream inputs to the Hippo pathway are thought to be context and cell type specific, targeting these various components could serve as a therapeutic approach for refining Hippo-Yap signaling in the heart. Here, we provide an overview of the emerging regulatory inputs to the Hippo pathway as they relate to mammalian cardiomyocytes and heart regeneration.